Abstract:

Disease is as old as life itself and the treatment thereof ancient too. A disease that still claims over a million lives annually and is considered a health problem in approximately 90 countries is malaria, even though it was discovered over a hundred years ago. Malaria has however been treated successfully with numerous anti-malarial drugs such as Fansidar®.
Fansidar® contains 500 mg sulfadoxine and 25 mg pyrimethamine and is used as second line treatment for malaria. Research has shown that African children can be protected against malaria by means of prophylaxis. In Gambia children were treated with a pyrimethamine and dapsone combination and the mortality decreased by 35% while in Malawi the sulfadoxine-pyrimethamine combination administered to pregnant women reduced placental malaria by 72%. However, for any pharmaceutical product to be effective in the treatment of disease, it must be thoroughly tested and submitted to the various standards to prove the safety and efficacy of such a product. These tests and standards are set in international pharmacopoeias and a product must comply with the acceptance criteria for that particular product.
During this study the emphasis fell on the dissolution test of the sulfadoxine-pyrimethamine combination tablet as stipulated by the USP. The pyrimethamine component constantly fails to comply with the dissolution requirements and it was decided that an alternative dissolution medium should be considered, which set the aim of this study. Furthermore it was suspected that sulfadoxine impurities interfered with the pyrimethamine peak in the HPLC chromatogram, as it appeared to produce a false positive peak.
For this purpose the USP method was used as a foundation to develop an analytical method with a more alkaline mobile phase by adjusting the pH. Because of this, the pyrimethamine peak was forced to appear after the sulfadoxine peak, preventing the impurities of the latter to affect the pyrimethamine peak. The results obtained from the modified analytical method was compared to that of the original analytical method and proved to be the better of the two as it produced best results. Three different media were tested with the new as well as the original analytical method and although the overall % RSD obtained for sulfadoxine didn't vary much for the two methods, pyrimethamine produced a much smaller % RSD with the new method.
With the new method as method of choice, dissolution tests of the innovator product (Fansidar®) and a generic (Falcistat®) were performed in three media (PBS pH 6.8, 0.1 N HCI and water). For both Fansidar® and Falcistat® 0.1 N HCI produced the best results as this was the only
medium in which both active ingredients complied with the dissolution criteria, hence 0.1 N HCI was considered the medium of choice.
Hereafter, stability test dissolutions were performed on both Fansidar® and Falcistat® to ensure the stability of sulfadoxine and pyrimethamine in the medium. The two concentrations used for these dissolution tests were 0.01 N and 0.1 N HCI. The concentrations obtained for pyrimethamine didn't differ significantly however less then 50% sulfadoxine dissolved in 0.01 N HCI for both Fansidar® and Falcistat®. Even though the stability didn't deteriorate remarkably in either of the two cases, 0.1 N HCI was still considered the medium of choice as it produced the best results.
Other generic products were tested to confirm the findings. Using 0.1 N HCI as dissolution medium and the newly developed method, dissolution tests were performed on the seven generics and the results proved that the modified method was indeed the method of choice as was the case with 0.1 N HCI as dissolution medium. All the products complied with the dissolution criteria for sulfadoxine and pyrimethamine except for Dionsdar® (sulfadoxine failed to comply) and Tansidar® (both active ingredients failed to comply). It was decided to perform another dissolution test on Tansidar® using PBS as dissolution medium (USP dissolution medium). Again Tansidar® failed to comply with the dissolution criteria as sulfadoxine produced worse results with the second dissolution test whilst pyrimethamine didn't dissolve. It is suspected that the composition of the Tansidar® tablets might be in question.
To conclude, it is believed that the success of 0.1 N HCI as dissolution medium in this study is due to the fact that it is the USP dissolution medium for pyrimethamine single component tablets. Hence, it would be the ideal solvent in this case as pyrimethamine doesn't dissolve easily or at all in most solvents whilst sulfadoxine wasn't negatively affected by the change in dissolution medium. Furthermore, the results obtained for the modified method were more accurate and of better quality as no impurities interfered with the small pyrimethamine peak.